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http://hdl.handle.net/10397/89947
Title: | Design, synthesis and biological evaluation of antimicrobial diarylimine and –amine compounds targeting the interaction between the bacterial NusB and NusE proteins | Authors: | Qiu, Y Chan, ST Lin, L Shek, TL Tsang, TF Barua, N Zhang, Y Ip, M Chan, PKS Blanchard, N Hanquet, G Zuo, Z Yang, X Ma, C |
Issue Date: | 15-Sep-2019 | Source: | European journal of medicinal chemistry, 15 Sept. 2019, v. 178, p. 214-231 | Abstract: | Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells were measured. Structure-activity relationship and quantitative structure–activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1–2 μg/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future. | Keywords: | Antimicrobial activity Diarylamine Diarylimine Inhibitor Methicillin-resistant Staphylococcus aureus Protein-protein interaction |
Publisher: | Elsevier Masson | Journal: | European journal of medicinal chemistry | ISSN: | 0223-5234 | EISSN: | 1768-3254 | DOI: | 10.1016/j.ejmech.2019.05.090 | Rights: | © 2019 Elsevier Masson SAS. All rights reserved. © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. The following publication Qiu, Y., Chan, S. T., Lin, L., Shek, T. L., Tsang, T. F., Barua, N., Zhang, Y., Ip, M., Chan, P. K.-s., Blanchard, N., Hanquet, G., Zuo, Z., Yang, X., & Ma, C. (2019). Design, synthesis and biological evaluation of antimicrobial diarylimine and –amine compounds targeting the interaction between the bacterial NusB and NusE proteins. European Journal of Medicinal Chemistry, 178, 214-231 is available at https://doi.org/10.1016/j.ejmech.2019.05.090. |
Appears in Collections: | Journal/Magazine Article |
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